Bringing innovative wound care polymer materials to the market: Challenges, developments, and new trends.

The development of innovative products for treating acute and chronic wounds has become a significant topic in healthcare, resulting in numerous products and innovations over time. The growing number of patients with comorbidities and chronic diseases, which may significantly alter, delay, or inhibit normal wound healing, has introduced considerable new challenges into the wound management scenario. Researchers in academia have quickly identified promising solutions, and many advanced wound healing materials have recently been designed; however, their successful translation to the market remains highly complex and unlikely without the contribution of industry experts. This review article condenses the main aspects of wound healing applications that will serve as a practical guide for researchers working in academia and industry devoted to designing, evaluating, validating, and translating polymer wound care materials to the market. The article highlights the current challenges in wound management, describes the state-of-the-art products already on the market and trending polymer materials, describes the regulation pathways for approval, discusses current wound healing models, and offers a perspective on new technologies that could soon reach consumers. We envision that this comprehensive review will significantly contribute to highlighting the importance of networking and exchanges between academia and healthcare companies. Only through the joint of these two actors, where innovation, manufacturing, regulatory insights, and financial resources act in harmony, can wound care products be developed efficiently to reach patients quickly and affordably.

Production of a novel poly(ɛ-caprolactone)-methylcellulose electrospun wound dressing by incorporating bioactive glass and Manuka honey.

Wound dressings produced by electrospinning exhibit a fibrous structure close to the one of the extracellular matrix of the skin. In this article, electrospinning was used to fabricate fiber mats based on the well-known biopolymers poly(ɛ-caprolactone) (PCL) and methylcellulose (MC) using benign solvents. The blend fiber mats were cross-linked using Manuka honey and additionally used as a biodegradable platform to deliver bioactive glass particles. It was hypothesized that a dual therapeutic effect can be achieved by combining Manuka honey and bioactive glass. Morphological and chemical examinations confirmed the successful production of submicrometric PCL-MC fiber mats containing Manuka honey and bioactive glass particles. The multifunctional fiber mats exhibited improved wettability and suitable mechanical properties (ultimate tensile strength of 3-5 MPa). By performing dissolution tests using simulated body fluid, the improved bioactivity of the fiber mats by the addition of bioactive glass was confirmed. Additionally, cell biology tests using human dermal fibroblasts and human keratinocytes-like HaCaT cells showed the potential of the fabricated composite fiber mats to be used as wound dressing, specially due to the ability to support wound closure influenced by the presence of bioactive glass. Moreover, based on the results of the antibacterial tests, it is apparent that an optimization of the electrospun fiber mats is required to develop suitable wound dressing for the treatment of infected wounds.

Electrospun PCL/PGS Composite Fibers Incorporating Bioactive Glass Particles for Soft Tissue Engineering Applications.

Poly(glycerol-sebacate) (PGS) and poly(epsilon caprolactone) (PCL) have been widely investigated for biomedical applications in combination with the electrospinning process. Among others, one advantage of this blend is its suitability to be processed with benign solvents for electrospinning. In this work, the suitability of PGS/PCL polymers for the fabrication of composite fibers incorporating bioactive glass (BG) particles was investigated. Composite electrospun fibers containing silicate or borosilicate glass particles (13-93 and 13-93BS, respectively) were obtained and characterized. Neat PCL and PCL composite electrospun fibers were used as control to investigate the possible effect of the presence of PGS and the influence of the bioactive glass particles. In fact, with the addition of PGS an increase in the average fiber diameter was observed, while in all the composite fibers, the presence of BG particles induced an increase in the fiber diameter distribution, without changing significantly the average fiber diameter. Results confirmed that the blended fibers are hydrophilic, while the addition of BG particles does not affect fiber wettability. Degradation test and acellular bioactivity test highlight the release of the BG particles from all composite fibers, relevant for all applications related to therapeutic ion release, i.e., wound healing. Because of weak interface between the incorporated BG particles and the polymeric fibers, mechanical properties were not improved in the composite fibers. Promising results were obtained from preliminary biological tests for potential use of the developed mats for soft tissue engineering applications.

Manuka honey and bioactive glass impart methylcellulose foams with antibacterial effects for wound-healing applications.

Wound dressings able to deliver topically bioactive molecules represent a new generation of wound-regeneration therapies. In this article, foams based on methylcellulose cross-linked with Manuka honey were used as a platform to deliver borate bioactive glass particles doped additionally with copper. Borate bioactive glasses are of great interest in wound-healing applications due to a combination of favorable features, such as angiogenic and antibacterial properties. The multifunctional composite providing the dual effect of the bioactive glass and Manuka honey was produced by freeze-drying, and the resulting foams exhibit suitable morphology characterized by high porosity. Moreover, the performed tests showed improved wettability and mechanical performance with the addition of bioactive glass particles. Dissolution studies using simulated body fluid and cell biology tests using relevant skin cells further proved the excellent bioactivity and positive effects of the foams on cell proliferation and migration. Most interestingly, by the dual release of Manuka honey and ions from the copper-doped bioactive glass, an antibacterial effect against E. coli and S. aureus was achieved. Therefore, the multifunctional foams showed promising outcomes as potential wound dressings for the treatment of infected wounds.

Cu, Zn doped borate bioactive glasses: antibacterial efficacy and dose-dependent in vitro modulation of murine dendritic cells.

Among emerging biomaterials, bioactive glasses (BGs) are being widely explored for various applications in tissue engineering. However, the effects of BGs (in particular BG ionic dissolution products) on immune cells and specifically on dendritic cells (DCs), which are the most potent antigen-presenting cells of the immune system, have not been previously investigated in detail. Such interactions between BGs and DCs must be assessed as a novel biocompatibility criterion for biomaterials, since, with the increased application possibilities of BGs, the modulation of the immune system may induce potential complications and undesired side effects. Indeed, the effects of BG exposure on specific immune cells are not well understood. Thus, in this study we investigated, for the first time, the effect of borate BGs doped with biologically active ions on specific immune cells, such as DCs and we further investigated the antibacterial properties of these borate BGs. The compositions of the borate BGs (B3) were based on the well-known 13-93 (silicate) composition by replacing silica with boron trioxide and by adding copper (3 wt%) and/or zinc (1 wt%). By performing an agar diffusion test, the antibacterial effect depending on the compositions of the borate BGs could be proved. Furthermore we found a dose-dependent immune modulation of DCs after treatment with borate BGs, especially when the borate BGs contained Zn and/or Cu. Depending on the ion concentration and the rise in pH, the phenotype and function of DCs were modified. While at low doses B3 and Zn-doped B3 BGs had no impact on DC viability, Cu containing BGs strongly affected cell viability. Furthermore, the surface expression of DC-specific activation markers, such as the major histocompatibility complex (MHC)-II, CD86 and CD80, was modulated. In addition, also DC mediated T-cell proliferation was remarkably reduced when treated with high doses of B3-Cu and B3-Cu-Zn BGs. Interestingly, the release of inflammatory cytokines increased after incubation with B3 and B3-Zn BGs compared to mock-treated DCs. Considering the essential role of DCs in the modulation and regulation of immune responses, these findings provide first evidence of phenotypic and functional consequences regarding the exposure of DCs to BGs in vitro.

Comparison of the Influence of 45S5 and Cu-Containing 45S5 Bioactive Glass (BG) on the Biological Properties of Novel Polyhydroxyalkanoate (PHA)/BG Composites.

Polyhydroxyalkanoates (PHAs), due to their biodegradable and biocompatible nature and their ability to be formed in complex structures, are excellent candidates for fabricating scaffolds used in tissue engineering. By introducing inorganic compounds, such as bioactive glasses (BGs), the bioactive properties of PHAs can be further improved. In addition to their outstanding bioactivity, BGs can be additionally doped with biological ions, which in turn extend the functionality of the BG-PHA composite. Here, different PHAs were combined with 45S5 BG, which was additionally doped with copper in order to introduce antibacterial and angiogenic properties. The resulting composite was used to produce scaffolds by the salt leaching technique. By performing indirect cell biology tests using stromal cells, a dose-depending effect of the dissolution products released from the BG-PHA scaffolds could be found. In low concentrations, no toxic effect was found. Moreover, in higher concentrations, a minor reduction of cell viability combined with a major increase in VEGF release was measured. This result indicates that the fabricated composite scaffolds are suitable candidates for applications in soft and hard tissue engineering. However, more in-depth studies are necessary to fully understand the release kinetics and the resulting long-term effects of the BG-PHA composites.

Interaction of MOPS buffer with glass-ceramic scaffold: Effect of (PO4 )3- ions in SBF on kinetics and morphology of formatted hydroxyapatite.

The international standard ISO 23317:2014 for the in vitro testing of inorganic biomaterials in simulated body fluid (SBF) uses TRIS buffer to maintain neutral pH. In our previous papers, we investigated the interaction of a glass-ceramic scaffold with TRIS and HEPES buffers. Both of them speeded up glass-ceramic dissolution and hydroxyapatite (HAp) precipitation, thereby demonstrating their unsuitability for the in vitro testing of highly reactive biomaterials. In this article, we tested MOPS buffer (3-[N-morpholino] propanesulfonic acid), another amino acid from the group of "Goods buffers". A highly reactive glass-ceramic scaffold (derived from Bioglass®) was exposed to SBF under static-dynamic conditions for 13/15 days. The kinetics and morphology of the newly precipitated HAp were studied using two different concentrations of (PO4 )3- ions in SBF. The pH value and the SiIV , Ca2+ , and (PO4 )3- concentrations in the SBF leachate samples were measured every day (AAS, spectrophotometry). The glass-ceramic scaffold was monitored by SEM/EDS, XRD, WD-XRF, and BET before and after 1, 3, 7, 11, and 13/15 days of exposure. As in the case of TRIS and HEPES, the preferential dissolution of the glass-ceramic crystalline phase (Combeite) was observed, but less intensively. The lower concentration of (PO4 )3- ions slowed down the kinetics of HAp precipitation, thereby causing the disintegration of the scaffold structure. This phenomenon shows that the HAp phase was predominately generated by the presence of (PO4 )3- ions in the SBF, not in the glass-ceramic material. Irrespective of this, MOPS buffer is not suitable for the maintenance of pH in SBF.

Bioactive glasses meet phytotherapeutics: The potential of natural herbal medicines to extend the functionality of bioactive glasses.

Herbal medicine, the use of plants or plant extracts with known beneficial biological effects to treat and/or prevent diverse health disorders, has been known for thousands of years. After their replacement by synthetic drugs in the beginning of the 20th century, plant derived therapeutic agents have been recently attaining more attention again. Phytotherapeutics, which can be extracted from a wide range of different herbal plants, are believed to have a broad spectrum of therapeutic effects and less negative side effects than synthetic drugs. On the other hand, it is often difficult to prove the therapeutic effect of herbal drugs due to their chemical complexity. In the last decade, research has focused increasingly on the relatively new concept of the combination of herbal drugs with modern engineered biomaterials in order to achieve synergy of their therapeutic effects. Even if several studies based on this concept have been published, no systematic overview of the performed investigations and their results is available. In this context, this review focuses on the combination of phytotherapeutics with bioactive glasses (BGs), which are bioactive and biodegradable materials capable of releasing biologically active ions being suitable for several applications as bone substituting and replacing materials as well as in the regeneration of soft and hard tissue. The literature search was carried out using the WEB OF SCIENCE® and SCOPUS® databases using a combination of relevant keywords. Besides giving an overview of the research done in the last years and summarizing the results obtained in those studies, the possible synergistic effects of herbal drugs in combination with BGs are critically discussed, and potential health risks are overviewed. Of all plant-derived drugs investigated so far, the coumarin family appears to be the one that has been most widely combined with BGs showing beneficial outcomes. Overall, the analysis of the literature has revealed the great potential of this organic-inorganic multi-functional system approach as an advantageous alternative to conventional medicine in several applications, but also highlights the need for more systematic in vivo studies to evaluate the effective time and dose dependent combined effects of BGs and phytotherapeutic agents.

Bioactive glass based scaffolds coated with gelatin for the sustained release of icariin.

Gelatin-coated, 3D sponge-like scaffolds based on 45S5 bioactive glass were produced using the foam replication technique. Compressive strength tests of gelatin-coated samples compared to uncoated scaffolds showed significant strengthening and toughening effects of the gelatin coating with compressive strength values in the range of cortical bone. Additionally, the crosslinked gelatin network (using either caffeic acid or N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC)/N-hxdroxysuccinimide (NHS) as crosslinking agent) was shown to be a suitable candidate for the sustained release of the bioactive molecule icariin. Concerning bioactivity of the produced scaffolds, characterization by FTIR and SEM indicated the formation of hydroxyapatite (HA) in all samples after immersion in simulated body fluid (SBF) for 14 days, highlighting the favorable combination of mechanical robustness, bioactivity and drug delivery capability of this new type of scaffolds.

Highly Porous Polymer-Derived Bioceramics Based on a Complex Hardystonite Solid Solution.

Highly porous bioceramics, based on a complex hardystonite solid solution, were developed from silicone resins and micro-sized oxide fillers fired in air at 950 °C. Besides CaO, SrO, MgO, and ZnO precursors, and the commercial embedded silicone resins, calcium borate was essential in providing the liquid phase upon firing and favouring the formation of an unprecedented hardystonite solid solution, corresponding to the formula (Ca0.70Sr0.30)2(Zn0.72Mg0.15Si0.13) (Si0.85B0.15)2O7. Silicone-filler mixtures could be used in the form of thick pastes for direct ink writing of reticulated scaffolds or for direct foaming. The latter shaping option benefited from the use of hydrated calcium borate, which underwent dehydration, with water vapour release, at a low temperature (420 °C). Both scaffolds and foams confirmed the already-obtained phase assemblage, after firing, and exhibited remarkable strength-to-density ratios. Finally, preliminary cell tests excluded any cytotoxicity that could be derived from the formation of a boro-silicate glassy phase.

Gelatin coating increases in vivo bone formation capacity of three-dimensional 45S5 bioactive glass-based crystalline scaffolds.

Recent studies have demonstrated that surface characteristics, porosity, and mechanical strength of three-dimensional 45S5-type bioactive glass (BG)-based scaffolds are directly correlated with osteogenic properties. Three-dimensional BG-based scaffolds obtained from maritime natural sponges (MNSs) as sacrificial templates exhibit the required morphological properties; however, no in vivo data about the osteogenic features are available. In this study, uncoated (Group A) and gelatin-coated (Group B) crystalline MNS-obtained BG-based scaffolds were evaluated mechanically and seeded with human mesenchymal stem cells prior to subcutaneous implantation in immunodeficient mice. Before implantation and after explantation, micro-computed tomography scans were conducted, and scaffolds were finally subjected to histomorphometry. Scaffolds of both groups showed bone formation. However, Group B scaffolds performed distinctly better as indicated by a significant increase in scaffold volume (8.95%, p = 0.039) over the implantation period compared with a nonsignificant increase of 5.26% in Group A scaffolds in micro-computed tomography analysis. Furthermore, percentage bone area was 10.33% (±1.18%) in the Group B scaffolds, which was significantly (p = 0.007) higher compared with the 8.53% (±0.77%) in the Group A scaffolds in histomorphometry. Compressive strength was enhanced significantly by gelatin coating (9 ± 2 vs. 4 ± 1 MPa; p = 0.029). The presence of gelatin on the remnant parts was verified by scanning electron microscopy and X-ray spectroscopy, demonstrating the coatings' resilience. MNS-obtained BG-based scaffolds were thus confirmed to exhibit osteogenic properties in vivo that can significantly be enhanced by gelatin coating.

Electrophoretic Deposition of Bioadaptive Drug Delivery Coatings on Magnesium Alloy for Bone Repair.

Biodegradable polymer coatings on magnesium alloys are attractive, as they can provide corrosion resistance as well as additional functions for biomedical applications, e.g., drug delivery. A gelatin nanospheres/chitosan (GNs/CTS) composite coating on WE43 substrate was fabricated by electrophoretic deposition with simvastatin (SIM) loaded into the GNs. Apart from a sustained drug release over 28 days, an anticorrosion behavior of the coated WE43 substrates was confirmed by electrochemical tests. Both the degradation and corrosion rates of the coated substrate were significantly minimized in contrast to bare WE43. The cytocompatibility of the coated samples was analyzed  both quantitatively and qualitatively. Additionally, the osteogenic differentiation of MC3T3-E1 cells on SIM-containing coatings was assessed by measuring the expression of osteogenic genes and related proteins, alkaline phosphatase (ALP) activity, and extracellular matrix mineralization, showing that the SIM-loaded composite coating could upregulate the expression of osteogenic genes and related proteins, promote ALP activity, and enhance extracellular matrix mineralization. In summary, the SIM-loaded GNs/CTS composite coatings were able to enhance the corrosion resistance of the WE43 substrate and promote osteogenic activity, thus demonstrating a promising coating system for modifying the surface of magnesium alloys targeted for orthopedic applications.